The proposed research will explore the significance of intracellular carrier proteins in the transport of endocannabinoids and will develop novel ligands that can modulate brain endocannabinoid levels. Endocannabinoids, including anandamide and 2-arachidonoyl glycerol, are neurolipids involved in cell signaling. They affect pain sensing, food intake, and reward mechanisms. Specific transporter and/or carrier protein(s) have been implicated in the transport of endocannabinoids to their intracellular inactivation sites In this proposal, we shall use nuclear magnetic resonance (NMR) spectroscopy to explore the structural and binding characteristics of two lipid carrier proteins, human brain fatty acid bindin protein (FABP7) and epidermal FABP (FABP5), to a range of selected ligands including the endocannabinoids and several widely used endocannabinoid transport inhibitors. The information will be used to derive structure activity relationships (SAR) of these two target proteins. This SAR by NMR approach will guide the development of potent FABP7 ligands as well as FABP7/5 dual inhibitors as putative drug candidates which act through the elevation of endocannabinoid levels. The conclusion of the proposed research will lead to a greater understanding of the endocannabinoid system and represent first step towards a potential new pharmacotherapy utilizing the inhibition of FABPs as a new therapeutic modality for treating pain, substance abuse/drug addiction and other disorders. PUBLIC HEALTH RELEVANCE: This research aims to increase our understanding of the role of cytosolic carrier proteins in the transport of endocannabinoids in the brain. These endocannabinoids are involved in cell signaling and affect pain sensitization, food intake, and reward mechanisms involved in drug addiction. The work set forth is intended to explore the structure and binding characteristics of two carrier proteins that belong to the fatty acid binding protein family, brain FABP (FABP7) and epidermal FABP (FABP5), and to develop selective FABP ligands as putative drug candidates for pain relief and drug addiction.